Within the therapeutic group of non-steriod antiinflammatories propionic acid derivatives occupy an outstanding place from both the therapeutic and commercial points of view.
Within this subgroup we can distinguish first of all ibuprofen (1), which was the first of a series in which we can today find naproxen (2), ketoprofen (3) and fenbufen (4) among others. 
The pharmacodynamic characteristics of all these products is similar, which they present in varying degrees of antiinflammatory, antithermic, analgesic and antiplatlet activity, all of them being non-selective inhibitors of ciclooxygenases (Cox I y Cox II) (Terapxc3xa9utica farmacolxc3x3gica del dolor. Jesxc3xas Flores 1993. Ed. EUNSA. Pamplona 1993. Coleccixc3x3n clxc3xadnica de la salud. Capitulo 5, pag: 121-156.).
The structural analogy between compounds (I) and (VI) (the latter being originally found and described from a fern xe2x80x9cAsplenium onopterisxe2x80x9d) has led us to a pharmacological study of the two series of functionalised molecules starting from 
in accordance with that shown in diagrams 1 and 2.
The central idea of the present invention therefore consists of obtaining a series of molecules on the basis of an adequate functionalisation using compound VI of Diagram 1 and using the corresponding derivatives of the aromatic rings, benzene and naphthalene, as functionalised syntones.
The cell, the structural and functional unit of all living beings, is governed by a series of mechanisms that take decisions which in turn determine different conducts: proliferation, differentiation, activation, senescence and apoptosis. In higher organisms, there are some tissues in which there exist stem cells that generate the functional mature cells by proliferation and differentiation.
Within the systems of higher organisms, the immunological system constitutes an essential defence mechanism for preserving the viability of the individual. Multicellular beings, including humans, find themselves in an environment with a great many microorganisms that can penetrate into their interior and use them for their own growth. The immune system is capable of recognising microorganisms and triggering an effector response leading to their destruction or functional cancellation. Moreover, multicellular beings undergo errors in cell proliferation processes and they accumulate mutations that lead to the tumoral transformation of some of their components. The immune system is also capable of recognising cells that have undergone neoplastic transformation and of successfully suppressing tumoral growth and dissemination. Nevertheless, the effector capacity of the immune system can provoke inflammatory tissue alterations with lesions to parenchymatous components. These processes are accompanied by infiltration and proliferation of cells from the immune system into the tissues. Some originate in the response to infectious agents and can be acute and systemic, such as sepsis and multiorganic inflammatory response, or they can be chronic and localised such as hepatitis, tubercular arthritis, etc. Other inflammatory processes mediated by the immune system are those known as autoimmune, which are triggered in the presence of the actual components of the organism, such as rheumatoid arthritis, inflammatory disease of the digestive tract, etc. As a cellular system, the immune system can also undergo tumoral transformations giving rise to malign lymphoproliferative syndromes. The immune system can also participate in aptogenis of tissue damage by chronic processes such as some demencias and arteriosclerosis.
In the analysis of immunological responses, a distinction is drawn between natural or non-specific immunity and acquired or specific immunity. The latter is in turn divided into tumoral immunity characterised by the production of antibodies by type B lymphocytes and in cell mediation response via T lymphocytes. The immunological response consists of a complex feedback network in which autocrine and paracrine mediators, cytokins, growth factors, etc., all play a role, in addition to the mediators responsible for connection with the endocrine system and the nervous system.
An essential element in the generation of the specific immunological response is the capacity to expand lymphocyte subpopulations by antigen stimulus determined via a complex process of recognition and processing of the antigen followed by a process of presentation to the effector cell that finally generates the response. This process can be summarised by saying that the proliferation of the subpopulations corresponding to the antigen is the essential property of mature lymphocytes (Assas A K, Lichtman A H, Pober J S. Cellular and Molecular Immunology. 2nd ed. W. B. USA: Sanders Company, 1994:31-3).
The cellular mechanisms for proliferation in turn imply a complex mechanism for the reception of signals external to the cell via membrane receptors, and the transmission of those signals to the cell nucleus in order to put into operation the mitotic mechanisms which likewise imply nuclear and cytoplasmatic processes (Metezeau P H, Ronot X, Le Loan-Merliquac Q, Ratinard M H. La Citometrie en Flux. In: Le Gorde Cellulaire. Paris: MEDSI/Mc Gram Hin, 1988:77-87).
The physiological mechanisms of the immunological system must necessarily include an availability of xe2x80x9cdefensivexe2x80x9d cells at sites where their activity is needed, hence the existence of xe2x80x9ccallxe2x80x9d mechanisms, circulation, recruitment and adhesion.
The efficiency of the immunological system is nevertheless subject to dysfunctions which can in general terms be separated into three fundamental types, as has been stated previously. Proliferative dysfunction, that in which a cell population or subpopulation proliferates out of control, giving rise to various types of leukaemias and lymphomas and other malign and benign lymphoproliferative syndromes. Functional dysfunction therefore implies an exacerbation of the response that gives to, for example, autoimmune pathologies due to errors in antigen recognition, or a decrease in the type of response giving rise to different situations of immunosuppression. One particular case consists of pathologies or situations of inflammation (chronic or acute) with the concomitant tissue destruction and functional alteration, which can be produced in the context of systemic autoimmune diseases or specific organs as well as in response to various infectious agents.
The pathology of the immunological system is in some aspects, and paradoxically so, parallel to the course of technological and social processes. For example, there can be no doubting the close relation between the development of the AIDS pandemic with social factors such as the enormous increase in displacements, the liberalisation of customs or the unemployment situation with its consequences of margination and drug addiction (Baiter M, Cohen J. International AIDs Meeting Infects a dose of realism. Science (New Fows) 1998;281:159-60., Mann J M, Tarantola D J. HIV 1998: the global picture. Sci Am 1998;279(1):82-3., Bartlett J G, Moore R D. Improving HIV therapy. Sci Am 1998;279(1):84-7).
Another important factor of immunological pathology is the development of the chemical industry and environmental contamination which propitiates the development of allergies and immunotoxicity (Descotes J. Immunotoxicology of drugs and chemicals. Elsevier Press, 1990., Herchman E, Kimber I, Purches IFH. Immunotoxicology: Suppressive and stimulatory effect of drugs and environmental chemicals on the immune system. Arch Toxicol 1989;63:257-73).
Finally, we can mention that, at least in developed countries, the increase in life expectancy, changes in nutrition, modifications to interactions with infectious agents, the present-day life-style, have all been associated with a greater incidence and prevalence of autoimmune disease and autoimmunity with inadequate recognition of tissues, which are seen as xe2x80x9cnot one""s ownxe2x80x9d, as in rheumatoid arthritis (Lugmano R, Gordon C; Bacon P. Clinical Pharmacology and modificator of autoimmunity and inflammatorion in rheumatoid disease. Drugs 1994;47(2):259-83), autoimmune diabetes (Riestra Moriegue J L, Guerro Silva R, Fernandez Sxc3xa1nchez J A, Balio Hernxc3xa1ndez J, Rodriguez Pxc3xa9rez A. Revisixc3x3n de los immunesupresores en el tratamiento de la artritis reumatoide. Inflamacixc3x3n 1993;IV (6):368-81), etc.
Finally, among the aspects tied to technological and environmental development, we can mention the repercussions of exposure to ionising radiations.
Knowledge of the immunological mechanisms and the growing social repercussions of immunological pathologies have, in the last 30 years, led to the development of substances capable of therapeutically manipulating the immunological system (immunomodulators).
In short, we have to understand that immunological dysfunction is always ambivalent and the development of the suppression of some of the functions can occasion the exacerbation of others (and vice versa), and that this implies a special difficulty in the effective therapeutic manipulation of the immunological system.
One of the most surprising pharmacological facts is the structural disparity of the different types of products specifically classified as immunomodulators (Werner G F, Jolle""s P. Immunostimulating agents: what next? A review of their present and potential medical applications. Eur J Biochem.1996;242:1-19), even leaving to one side antiinflammatory substances and cytostatic agents (antimitotics).
On the basis of these considerations, there is a clear possibility of designing new active principles provided with pharmacological activity towards the immunological system based on some type of interference with uncontrolled processes of differentiation, activation, proliferation or programmed cell death (apoptosis).
One of the essential aspects already mentioned and to which this present invention is especially tied is the capacity of one type of immune cell, the lymphocytes, to enter into proliferation (mitosis) via different stimuli for which it has specific receptors.
So, one way of blocking this proliferative phenomenon could be to block one or several of the activation mechanisms, i.e., the blocking of specific receptors, to interference with the transmitters of the signal as far as the cell nucleus.
The present invention describes the obtaining of a set of substances capable of interfering with different mechanisms for the transmission of activation signals in immunocompetent cells, thereby blocking processes of cell proliferation. This will be able to permit the therapeutic use of those substances in processes accompanied by an inadequate proliferation of immune system cells. This implies processes of inflammatory tissue infiltration with lymphocyte proliferation such as what are known as autoimmune diseases and inadequate responses to infectious agents with induction of tissue damage mediated by the immune system, and evidently also including malign and benign lymphoproliferative processes. The lymphocyte proliferation also participates pathogenically in various chronic diseases such as amyloidosis, Alzheimer type demencia, arteriosclerosis, etc., which could benefit from the use of these agents.
The design of such substances starts from the presence of 3-(4-hdroxyphenyl)propionic acid (II) in methanolic extracts of the fern Asplenium onopteris (Hernxc3xa1ndez Silva H. Aportacixc3x3n a la fitoquxc3xadmica de helechos. Sxc3xadntesis y funcionalizacixc3x3n de una nueva molxc3xa9cula natural bioactiva. Tesis Doctoral, Universidad de La Laguna (1996)). The structural similarity of this molecule to certain non-steriod antiinflammatories led to its use as lead product for its functionalisation and pharmacological evaluation.
There exist antecedents of pharmacological activity of lactones, in particular cytostatic activity of sesquiterpene lactones (Kupchan S M, Eakin M A, Thomas A M. Tumour inhibitors. 69. Structure-cytotoxicity relationships among the sesquiterpene lactones. J Med Chem 1971;14(12):1147-52., 13., Nakagawa M, Hirota A, Sakai H., Isogai A.Terrecyclic acid A, a new antibiotic from Aspergillus terreus. I. Taxonomy, production, and chemical and biological properties. J Antibiot 1982;35:778-82).
Another antecedent consists of lactones derived from kava, a plant used in traditional medicine in Indonesia (Lebot V, Levesque J. El Kava un remedio contra el estrxc3xa9s?. Mundo Cientxc3xadfico 1987;178:366-70).
These products are being tested in a wide field of clinical situations such as clinical depressions and myorelaxation, though hepatic and blood toxicity has recently been described for this type of product (Jappe V, Framke I, Reinhold D, Gollmick H Sebotropia drug reaction resventing from kava-kava extract therapy. A new entity? J Am Acad Dermatology 1988; 38(1):104-6).
Antiproliferative products must necessarily act at the level of controlling the cell cycle, which means that it is necessary to have a knowledge of the biochemical mechanisms involved in it. This permits (and will permit) the design of inhibitors with greater safety and specificity (Morgan D O. Principles of CDK regulation. Nature 1995;374:131-4., Edgar B A, Lehner C A. Developmental control of cell cycle regulators: A fly""s perspective. Science 1996;374:1646-52).
The outline has very recently been published of the general synthesis of a xe2x80x9clibraryxe2x80x9d of protein-kinase inhibitor products with the idea of obtaining therapeutic effects starting from specific blockings of enzyme systems responsible for the progression of the cell cycle (Gray N, Wodicka L, Thunnissen A, Norman T, Kwon S, Espinoza F H et al. Exploiting chemical libraries, structure and genomics in the search for kinase inhibitors. Science 1998; 281:533-8).
Various indole derivatives have recently also recently been discovered (Garoti L, Roberti M, Rossi T, Castelli M, Malagolis M. Synthesis and antiproliferative activity of 3-substituted 1H indole [3,2-d]-1,2,3-triazin-4(3H)-ones. Eur J Med Chem 1993; 33:43-6.) as have those of gallic acid (Serrano A, Palacios C, Roy G, Crespxc3x3n C, Villar M, Nocito M et al. Derivatives of gallic acid induce apoptosis in tumoral cell lines and inhibit lymphocyte proliferation. Arch Bioch Biophysicos 1998;330(1):49-54.), containing this pharmacological activity, though via different mechanisms.
From everything stated above, it clearly emerges that the maladjustment of the transduction paths for signals controlling cell growth can lead to the development of tumoral pathologies. Consequently, the possibility exists of a design of drugs aimed specifically at blocking the transduction of signals (whether these be of the protein-protein type or of the xe2x80x9ccascade phosphylationxe2x80x9d type (Saltiel A R, Samyer T K. Targeting signal transduction in the discovery of antiproliferative drugs. Chem and Biology 1996;3(11):887-93.). Finally, mention is made of novel antecedents in relation to antiproliferative substances (Babit-Le-Bouteiller C, Jamme M F, David M, Silve S, Lanau C, Dhers C et al. Antiproliferative effects of SR31747A in animal cell lines are mediated by inhibition of cholesterol biosynthesis at the sterol isomerase step. Eur J Biochem 1998;256:342-59., Dell C P. Antiproliferative naphthopyrans: biological activity, mechanistic studies and therapeutic potential. Current Medicinal Chemistry 1998;5:179-94., Kamei H, Koide T, Kojima T, Hashimoto Y, Hasegawa M. Inhibition of cell growth in cultures by quinones. Cancer Biotherapy and Radiopharmaceuticals 1998;13(3):185-188., Zafra-Polo M C, Figadere B, Gallardo T, Tormo J R, Cortes D. Natural acetogenins from annonaceae, synthesis and mechanism of action. Phytochemistry 1998;48(7):1087-117., Cheviron N, Grillon C, Carlier M F, Wdzieczak-Bakala J. The antiproliferative activity of the tetrapectide acetyl-N-SerAspLysPro, an inhibitor of haematopoietic stem cell proliferation, is not mediated by a thymosin xe2x96xa14-like effect on actin assembly. Cell Prolif 1996;29:437-46).